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Eye Development Error Causes Cataracts, Glaucoma

Researchers have found a common mutation in patients with pediatric
cataracts that could broaden our understanding of how the eye develops.

A cataract is a clouding of the eye lens—the transparent
tissue that focuses light onto the retina at the back of the eye,
where images are recorded. The lens is made mostly of water and
protein arranged to keep the tissue clear and let light pass through.
If the proteins begin to clump together, they can form a cataract
that clouds an area of the lens. This can happen as we age, but
about 1 in every 30,000 babies nationwide develops cataracts because
of mutations in their genetic code. Cataracts can be removed surgically,
but for infants this procedure increases their risk of developing
another eye disease, glaucoma.

In the new study, 2 research groups—led by Dr. Simon John
from Jackson Laboratory in Bar Harbor, Maine, and Dr. Richard L.
Maas of Brigham and Women's Hospital and Harvard Medical School
in Boston—found that a few human patients and a strain of
mice shared a malfunctioning gene, called TDRD7, that
led to juvenile cataracts. The research, which was funded partly
by NIH's National Eye Institute (NEI), National Institute for Child
Health and Human Development (NICHD) and National Institute for
General Medical Sciences (NIGMS), helped to uncover how lens development
is regulated. The findings appeared in the March 25, 2011, issue
of Science.

TDRD7 codes for a protein found in protein-RNA complexes
called RNA granules. In a process called transcription, DNA sequences
in genes are copied into more transient form as RNA. These "messenger
RNAs" (mRNAs) can be modified, stored or degraded before being
brought to the molecular machinery that translates the sequences
into proteins. RNA granules regulate mRNAs after they are transcribed.

To characterize the role of TDRD7 in lens development,
the researchers studied mice and chicks in which the TDRD7 gene
was experimentally suppressed. They discovered that expression
of TDRD7 is normally high in the developing lens. When TDRD7 was
removed, the expression of genes important for eye development
was significantly changed. In mice with experimentally suppressed TDRD7,
cataracts formed within weeks of birth. These animals also began
to develop glaucoma as they aged.

A process called oxidative stress has been previously suggested
to contribute to glaucoma by damaging drainage structures in the
eyes. The researchers demonstrated that TDRD7 mutations
led to a dramatic reduction in stress granules—a specific
type of RNA granule that helps protect against environmental stresses
like oxidation.

"This means that mutations in the TDRD7 gene could
cause a double jeopardy for childhood glaucoma," John explains. "First,
they cause cataract, and cataract extraction may raise oxidative
stress in the ocular drainage tissues. Second, they impair the
formation of protective stress granules in response to oxidative
stress."

Taken together, this research shows that TDRD7-containing RNA
granules are crucial for normal lens function. The findings are
one of the first examples of a posttranscriptional regulation mechanism
for organ development, opening up a whole new field of investigation.